LAUSR

Cytotoxic T lymphocytes (CTLs) kill virus-infected and cancer cells through T cell receptor (TCR) recognition. How CTLs terminate signaling and disengage to allow serial killing has remained a mystery. TCR activation triggers membrane specialization within the immune synapse, including the production of diacylglycerol (DAG), a lipid that can induce negative membrane curvature. We found that activated TCRs were shed into DAG-enriched ectosomes at the immune synapse rather than internalized through endocytosis, suggesting that DAG may contribute to the outward budding required for ectocytosis. Budding ectosomes were endocytosed directly by target cells, thereby terminating TCR signaling and simultaneously disengaging the CTL from the target cell to allow serial killing. Thus, ectocytosis renders TCR signaling self-limiting. Description Editor’s summary Cytotoxic T lymphocytes (CTLs) are serial killers that can destroy multiple target cells in succession. Using high-resolution three-dimensional imaging, Stinchcombe et al. found that T cell receptor (TCR) activation causes rapid membrane specialization at the immune synapse so that membrane containing activated TCRs buds off in a process known as “ectocytosis. ” As ectosomes bud off, CTLs and their target cells separate, allowing serial killing to proceed. Thus, in activated CTLs, ectocytosis renders TCR signaling self-limiting. —Stella M. Hurtley Activated T cell receptors are shed through ectocytosis, not endocytosis, at the immune synapse.